All publications cited herein are incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Cancers arising at mucosal barrier sites, particularly the lung, large intestine (LI), stomach and cervix, account for a considerable fraction of human malignancies (Siegel et al., 2012). One contributing factor to the colon's susceptibility to malignant transformation is its immunosuppressive environment (MacDonald et al., 2011) which is necessary for tolerance towards microbial and dietary antigens but also results in dampened anti-cancer immune responses (Revaz and Nardelli-Haefliger, 2005; Saleh and Trinchieri, 2011). Identifying physiologic factors capable of countering this inherent downside of local tolerance is critical for understanding and manipulating carcinogenesis at this, and possibly other, mucosal sites.
The production and handling of IgG are critical components of mucosal immunity, particularly in the LI where IgG accounts for a large fraction of homeostatic mucosal immunoglobulin secretion (Kozlowski et al., 1997). The presence of IgG in the intestinal lumen is associated with the actions of the bidirectional IgG transport receptor, FcRn (neonatal Fc receptor for IgG), which is expressed lifelong in most murine and human endothelial, epithelial and hematopoietic cells (Claypool et al., 2004; Zhu et al., 2001). FcRn is uniquely capable of delivering IgG into the lumen and also retrieving lumenal IgG and IgG containing immune complexes (IgG IC) which are delivered into the local immune system of the lamina propria (LP) (Claypool et al., 2004; Yoshida et al., 2004). FcRn within antigen presenting cells such as dendritic cells (DC) also plays a critical role in the processing of antigens delivered as IgG IC and actively promotes major histocompatibility complex (MHC) class I and class II restricted T cell responses (Baker et al., 2011; Qiao et al., 2008) which can alternatively promote anti-bacterial IgG-driven colitis (Kobayashi et al., 2009) and protect from mucosal pathogens (Qiao et al., 2008; Yoshida et al., 2006).
It is well accepted that cytotoxic CD8+ T cell-mediated responses are critical for efficient anti-tumor immunity (Pages et al., 2005) and FcRn has recently been shown to enable highly efficient cross-presentation of IgG-complexed antigens by CD8−CD11b+ DC (Baker et al., 2011). Given the abundance of both IgG and CD8−CD11b+ monocyte-derived DC in mucosal tissues, especially in the context of malignancy (Kozlowski et al., 1997; Ma et al., 2011; MacSween and Eastwood, 1980), the role of FcRn in homeostatic CD8+ T cell responses and as an effector of anti-cancer immune surveillance was examined Described herein are findings showing that FcRn ligation with IgG containing immune complexes (IgG IC) is directly involved in the production of IL-12, a key regulator of an immune response. Production of IL-12 may thus be targeted with agents that increase IL-12 production via altered FcRn/IgG interactions so as to treat cancer and/or infectious diseases or with agents that decrease IL-12 production via altered FcRn/IgG interactions so as to treat autoimmune diseases, therefore meeting a need for therapeutic agents to treat cancer, infectious diseases and autoimmune diseases.